Novel insights from adaptor protein 3 complex deficiency
Istituto di Medicina Molecolare Angelo Nocivelli and Clinica Pediatrica and Dipartimento di Scienze Biomediche e Biotecnologie, University of Brescia, Brescia, Italy. Journal of Allergy and Clinical Immunology
(Impact Factor: 11.48).
11/2007; 120(4):735-41; quiz 742-3. DOI: 10.1016/j.jaci.2007.08.039
Hermansky-Pudlak type 2 is an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding disorders, recurrent infections, and moderate/severe neutropenia. The disease is caused by mutations in the AP3B1 gene encoding for the beta3A subunit of the adaptor protein 3 (AP-3) complex. Because the expression of the beta3A subunit is normally ubiquitous, its deficiency leads to a precise phenotype in cells with a large number of intracellular granules, such as neutrophils, natural killer cells, cytotoxic T lymphocytes, platelets, and melanocytes. Given the AP-3 deficiency, the lysosomal membrane proteins are not appropriately sorted to the granules but are delivered to plasma membrane with subsequent effects on cell development and differentiation. Missorting of proteins (eg, tyrosinase) in melanocytes and platelets accounts for oculocutaneous albinism and bleeding disorders, respectively. Absence of AP-3 leads to low intracellular content of neutrophil elastase and consequently to neutropenia. Abnormal movement of lytic granules and reduced perforin content in cytotoxic T lymphocytes and natural killer cells account for their respective defects in cytolytic activity. It is likely that the investigation of the physiopathology of Hermansky-Pudlak type 2 syndrome will reveal nonredundant functions of this adaptor protein in the intracellular trafficking of membrane proteins.
Available from: Sara Scutera
- "AP-3 escorts proteins from the early trans-Golgi network to lysosomerelated organelles (Feng and others 1999; Dell'Angelica 2009). A mutation in the gene ADTB3A, which encodes for the b3A subunit, causes the Hermansky–Pudlak syndrome type 2 (HPS-2), an autosomal recessive inherited disease characterized by partial albinism, prolonged bleeding, and immunodeficiency (Badolato and Parolini 2007). "
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ABSTRACT: Adaptor protein-3 (AP-3) is a heterotetrameric complex, which regulates vesicular trafficking. Mutations of the
b3A subunit cause the Hermansky–Pudlak syndrome type 2 (HPS-2), a rare genetic disease characterized byalbinism, platelet defects, and recurrent infections. Likewise, pearl mice, which lack functional AP-3, show
several HPS-2 defects. The AP-3 absence results in defective TLR trafficking and signaling in dendritic cells
(DC), but its effect on the efficiency of the in vivo antiviral response is unclear. We evaluated the impact of AP-3
deficiency on the distribution of DC subsets, interferon (IFN) production, and the susceptibility to murine
cytomegalovirus (MCMV) infection. Pearl mice showed a distribution and frequency of conventional (cDC) and
plasmacytoid DC (pDC) similar to that of wild-type mice both before and afterMCMV infection.Moreover, pearl
mice controlled MCMV infection even at high virus doses and showed a normal production of IFN-a. Since pDC,
but not cDC, from pearl mice showed an impaired IFN-a and tumor necrosis factor-a production in response to
prototypic DNA (MCMV and Herpes Simplex virus) or RNA (Vesicular Stomatitis virus) viruses in vitro, it is
likely that MCMV infection can be controlled in vivo independently of an efficient production of IFN-a by pDC,
and that the AP-3 complex has a minimal impact on protective antiviral responses.
Journal of Interferon & Cytokine Research 03/2015; 35(3):232-238. DOI:10.1089/jir.2013.0110 · 2.00 Impact Factor
Available from: Laura Dotta
- "In mammalian cells there are 4 types of adaptor protein complexes that are involved in cellular protein trafficking. In particular, AP-3 directs post-translational trafficking of intraluminal cargo proteins from the trans-Golgi network to lysosomes
[53-55]. The absence of the AP-3 complex impairs trafficking of lysosome-targeted proteins to and from lysosomes so that proteins trafficking to lysosomes will accumulate at the plasma membrane. "
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ABSTRACT: Hypopigmentation disorders that are associated with immunodeficiency feature both partial albinism of hair, skin and eyes together with leukocyte defects. These disorders include Chediak Higashi (CHS), Griscelli (GS), Hermansky-Pudlak (HPS) and MAPBP-interacting protein deficiency syndromes. These are heterogeneous autosomal recessive conditions in which the causal genes encode proteins with specific roles in the biogenesis, function and trafficking of secretory lysosomes. In certain specialized cells, these organelles serve as a storage compartment. Impaired secretion of specific effector proteins from that intracellular compartment affects biological activities. In particular, these intracellular granules are essential constituents of melanocytes, platelets, granulocytes, cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Thus, abnormalities affect pigmentation, primary hemostasis, blood cell counts and lymphocyte cytotoxic activity against microbial pathogens. Among eight genetically distinct types of HPS, only type 2 is characterized by immunodeficiency. Recently, a new subtype, HPS9, was defined in patients presenting with immunodeficiency and oculocutaneous albinism, associated with mutations in the pallidin-encoding gene, PLDN.
Hypopigmentation together with recurrent childhood bacterial or viral infections suggests syndromic albinism. T and NK cell cytotoxicity are generally impaired in patients with these disorders. Specific clinical and biochemical phenotypes can allow differential diagnoses among these disorders before molecular testing. Ocular symptoms, including nystagmus, that are usually evident at birth, are common in patients with HPS2 or CHS. Albinism with short stature is unique to MAPBP-interacting protein (MAPBPIP) deficiency, while hemophagocytic lymphohistiocytosis (HLH) mainly suggests a diagnosis of CHS or GS type 2 (GS2). Neurological disease is a long-term complication of CHS, but is uncommon in other syndromic albinism. Chronic neutropenia is a feature of HPS2 and MAPBPIP-deficiency syndrome, whereas it is usually transient in CHS and GS2. In every patient, an accurate diagnosis is required for prompt and appropriate treatment, particularly in patients who develop HLH or in whom bone marrow transplant is required. This review describes the molecular and pathogenetic mechanisms of these diseases, focusing on clinical and biochemical aspects that allow early differential diagnosis.
Orphanet Journal of Rare Diseases 10/2013; 8(1):168. DOI:10.1186/1750-1172-8-168 · 3.36 Impact Factor
Available from: Subarna Chakravorty
- "HPS type 2 (HPS2) is a very rare subtype of HPS in which reduced pigmentation and platelet dysfunction are accompanied by neutropenia [4-13] and in some cases, reduced CTL and NK cell cytotoxicity. This may manifest as increased susceptibility to viral infection and rarely, haemophagocytic lymphohistiocytosis (HLH) in response to viral infection [7,8,12]. "
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Hermansky-Pudlak syndrome 2 (HPS2; OMIM #608233) is a rare, autosomal recessive disorder caused by loss-of-function genetic variations affecting AP3B1, which encodes the β3A subunit of the adaptor-related protein complex 3 (AP3). Phenotypic characteristics include reduced pigmentation, absent platelet dense granule secretion, neutropenia and reduced cytotoxic T lymphocyte (CTL) and natural killer (NK) cell function. To date HPS2 has been associated with non-synonymous, stop-gain or deletion-insertion nucleotide variations within the coding region of AP3B1.
We describe a consanguineous female infant with reduced pigmentation, neutropenia and recurrent infections. Platelets displayed reduced aggregation and absent ATP secretion in response to collagen and ADP, indicating a platelet dense granule defect. There was increased basal surface expression of CD107a (lysosome-associated membrane protein 1(LAMP-1)) on NK cells and CTLs from the study subject and a smaller increase in the percentage of CD107a positive cells after stimulation compared to most healthy controls. Immunoblotting of protein extracts from EBV-transformed lymphoblasts from the index case showed absent expression of full-length AP-3 β3A subunit protein, confirming a phenotypic diagnosis of HPS2.
The index case displayed a homozygous pericentric inv(5)(p15.1q14.1), which was also detected as a heterozygous defect in both parents of the index case. No loss of genetic material was demonstrated by microarray comparative genome hybridisation at 60kb resolution. Fluorescence in-situ hybridisation using the 189.6kb probe RP11-422I12, which maps to 5q14.1, demonstrated dual hybridisation to both 5q14.1 and 5p15.1 regions of the inverted Chr5. The RP11-422I12 probe maps from intron 1 to intron 16 of AP3B1, thus localising the 5q inversion breakpoint to within AP3B1. The probe RP11-211K15, which corresponds to an intergenic region on 5p also showed dual hybridisation, enabling localisation of the 5p inversion breakpoint.
This case report extends the phenotypic description of the very rare disorder HPS2. Our demonstration of a homozygous Chr5 inversion predicted to disrupt AP3B1 gene provides a novel pathogenic mechanism for this disorder.
BMC Medical Genetics 04/2013; 14(1):42. DOI:10.1186/1471-2350-14-42 · 2.08 Impact Factor
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